Chemokines are a family of relatively small proteins that have been implicated as mediators of acute and chronic inflammation. Roles in other immunoregulatory processes have been reported for certain chemokines as well.
One branch of the chemokine family is characterized by the presence of an amino acid between the first two of four conserved cysteines, whereas a second branch lacks any amino acid between those two cysteine residues. The first branch has been designated the C-X-C branch or a subfamily, and the second is known as the C-C branch or .beta. subfamily (Michiel, Bio/Technology 11:739, June 1993).
Chemokines have chemotactic properties, attracting certain cells of the immune system to sites of tissue injury and infection. Most of the .alpha. subfamily members attract and activate neutrophils, whereas .beta. subfamily members attract monocytes. Certain .beta. subfamily members additionally have been reported to recruit basophils, eosinophils or lymphocytes.
The roles chemokines play in various disorders is discussed in Baggiolini et al. (Advances in Immunology 55:97-179, 1994). Among the disorders believed to be mediated or exacerbated by one or more chemokines are inflammatory conditions of the lung (including inflammation associated with allergy or asthma) and skin (e.g., psoriasis). High levels of certain chemokines have been detected in the synovial fluid of inflamed joints in rheumatoid arthritis and osteoarthritis patients.
The chemokine macrophage inflammatory protein-1.beta. (MIP-1.beta.) suppresses hematopoietic stem cell proliferation, which has been suggested to contribute to anemia in malaria patients (Burgmann et al., Clinical Immunology and Immunopathology 76:32-36, 1995). The proinflammatory action of Interleukin-8 (IL-8) may play a role in deleterious host responses to sepsis (Marty et al., Crit. Care Med. 22:673-679, 1994). The possibility that monocyte chemoattractant protein-1 (MCP-1) and other C-C chemokines are involved in cardiovascular disease, through recruitment of monocytes into atherosclerotic areas, has been the subject of several studies (Baggiolini et al., supra, at page 146).
Inhibitors of chemokines would be useful in treating the disorders discussed above. A compound that inhibits more than one chemokine would be an especially desirable therapeutic agent.